Angel Arnaout1,2,3, Susan J Robertson4, Gregory R Pond5, Hoyun Lee6,7, Ahwon Jeong2, Luisa Ianni2,8, Lynne Kroeger8, John Hilton2,3,9, Stuart Coupland10, Chloe Gottlieb10, Bernard Hurley10, Anne McCarthy11, Mark Clemons12,13,14. 1. Division of Surgical Oncology, Department of Surgery, Ottawa Hospital, Ottawa, Canada. 2. Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada. 3. Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada. 4. Division of Anatomical Pathology, Ottawa Hospital, Ottawa, Canada. 5. Department of Oncology, McMaster University, Hamilton, Canada. 6. Health Sciences North Research Institute, Sudbury, Canada. 7. Department of Medicine, University of Ottawa, Ottawa, Canada. 8. Ottawa Hospital Breast Health Centre, Ottawa, Canada. 9. Division of Medical Oncology, Department of Medicine, University of Ottawa and Ottawa Hospital Cancer Center, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Canada. 10. Department of Ophthalmology, University of Ottawa, Ottawa, Canada. 11. Division of Infectious Diseases, Department of Medicine, Ottawa Hospital, Ottawa, Canada. 12. Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada. mclemons@toh.ca. 13. Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada. mclemons@toh.ca. 14. Division of Medical Oncology, Department of Medicine, University of Ottawa and Ottawa Hospital Cancer Center, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Canada. mclemons@toh.ca.
Abstract
PURPOSE:Chloroquine has demonstrated anti-tumor activities through autophagy inhibition and cell cycle disruption. This study aimed to assess the effect of single-agent chloroquine on breast tumor cellular proliferation in a randomized, phase II, double-blind, placebo-controlled, pre-surgical window of opportunity trial. METHODS:Patients with newly diagnosed breast cancer were randomized 2:1 to chloroquine 500 mg daily or placebo for 2- to 6-weeks prior to their breast surgery. The primary outcome was the relative change in measures of proliferation (Ki67) in primary breast cancer cells pre- and post-treatment. Adverse events and toxicity profiles were also evaluated. RESULTS:From September 2015 to December 2016, 70 patients were randomized [46 (66%) chloroquine and 24 (34%) placebo]. Ten patients who were randomized to chloroquine withdrew from study due to adverse events. Mean duration of drug intake was 15 days (range 14-29 days). There were no significant differences between the chloroquine or placebo arms with respect to either the percentage change (- 0.4 vs. - 1.2, p = 0.088) or absolute change (- 2.0% vs. - 5.2%, p = 0.066) in Ki67 index pre- and post-drug treatment. Although adverse effects were minimal and all classified as grade 1, the effects were significant enough to cause nearly 15% of patients to discontinue therapy. CONCLUSIONS: Treatment with single-agent chloroquine 500 mg daily in the preoperative setting was not associated with any significant effects on breast cancer cellular proliferation. It was, however, associated with toxicity that may affect its broader use in oncology.
RCT Entities:
PURPOSE:Chloroquine has demonstrated anti-tumor activities through autophagy inhibition and cell cycle disruption. This study aimed to assess the effect of single-agent chloroquine on breast tumor cellular proliferation in a randomized, phase II, double-blind, placebo-controlled, pre-surgical window of opportunity trial. METHODS:Patients with newly diagnosed breast cancer were randomized 2:1 to chloroquine 500 mg daily or placebo for 2- to 6-weeks prior to their breast surgery. The primary outcome was the relative change in measures of proliferation (Ki67) in primary breast cancer cells pre- and post-treatment. Adverse events and toxicity profiles were also evaluated. RESULTS: From September 2015 to December 2016, 70 patients were randomized [46 (66%) chloroquine and 24 (34%) placebo]. Ten patients who were randomized to chloroquine withdrew from study due to adverse events. Mean duration of drug intake was 15 days (range 14-29 days). There were no significant differences between the chloroquine or placebo arms with respect to either the percentage change (- 0.4 vs. - 1.2, p = 0.088) or absolute change (- 2.0% vs. - 5.2%, p = 0.066) in Ki67 index pre- and post-drug treatment. Although adverse effects were minimal and all classified as grade 1, the effects were significant enough to cause nearly 15% of patients to discontinue therapy. CONCLUSIONS: Treatment with single-agent chloroquine 500 mg daily in the preoperative setting was not associated with any significant effects on breast cancer cellular proliferation. It was, however, associated with toxicity that may affect its broader use in oncology.
Entities:
Keywords:
Breast cancer; Chloroquine; Window of opportunity clinical trial
Authors: Jan Hraběta; Marie Belhajová; Hana Šubrtová; Miguel Angel Merlos Rodrigo; Zbyněk Heger; Tomáš Eckschlager Journal: Int J Mol Sci Date: 2020-06-20 Impact factor: 5.923
Authors: Katelyn A Pastick; Elizabeth C Okafor; Fan Wang; Sarah M Lofgren; Caleb P Skipper; Melanie R Nicol; Matthew F Pullen; Radha Rajasingham; Emily G McDonald; Todd C Lee; Ilan S Schwartz; Lauren E Kelly; Sylvain A Lother; Oriol Mitjà; Emili Letang; Mahsa Abassi; David R Boulware Journal: Open Forum Infect Dis Date: 2020-04-15 Impact factor: 3.835